tbuckley/cabot-search huggingface dataset:
ctDNA analysis of NTRK fusion and mechanisms of acquired resistance to TRK inhibitors.
Authors: Karthigayini Sivaprakasam, Guilherme Harada, Noura J. Choudhury, Casey Savin, Ronak H. Shah, Michael F. Berger, Alexander E. Drilon
Journal: Journal of Clinical Oncology (2023)

3062 Background: The regulatory approval of TRK tyrosine kinase inhibitors (TKIs) represented a landmark in tissue-agnostic drug development. Adult and pediatric patients harboring NTRK fusions derive meaningful clinical benefits from the first-generation TRK TKIs larotrectinib and entrectinib. However, characterizing NTRK fusions and resistance mechanisms to TRK TKIs by circulating tumor DNA (ctDNA) remains to be studied. Methods: Patients with NTRK-fusion-positive tumors who received TRK TKIs and had ctDNA analyzed using next-generation sequencing (NGS) were retrospectively identified. Samples were collected at multiple time points, including pre-TRK TKI, on-treatment, and post-progression. Mechanisms of resistance to TRK TKIs were examined when post-progression ctDNA samples were available. Results: Twenty-seven patients, with a median age of 57 years (range 28-81) and 11 different cancer types were identified. Twenty-two patients (81%; 22/27) had at least one ctDNA-positive sample (tumor burden greater than 0). A total of 67 ctDNA samples were analyzed by MSKCC ACCESS ctDNA pipeline, of which 10 samples (15%; 10/67) were collected before any TRK TKI. Forty-two samples (63%; 42/67) had positive ctDNA and NTRK fusion was detected in 16 ctDNA samples (24%; 16/67), including 9 (56%) NTRK1 fusions and 7 (44%) NTRK3 fusions. Among the pre-TRK TKI samples (n=10), 2 samples (20%, 2/10) had NTRK fusions detected. A total of 8 patients had post-progression samples with a resistance mechanism identified, of which 5 patients received larotrectinib and 3 entrectinib. The ctDNA samples revealed 7 patients (88%; 7/8) with on-target resistance and 1 patient (12%; 1/8) with off-target resistance. Among on-target mutations identified, the most common involved the solvent front residue (86%, n=6/7: n=2 NTRK3 G623R, n=2 NTRK1 G595R, n=1 NTRK3 G623E, n=1 NTRK3 623L) followed by the xDFG motif (14%, n=1/7: n=1 NTRK1 G667C). Regarding off-target alterations, one patient developed a BRAF V600E mutation. Conclusions: The use of plasma ctDNA can improve the identification of NTRK fusions through non-invasive techniques and potentially identify subsequent resistance mechanisms after the administration of the TRK TKIs.
Effect of neoadjuvant chemotherapy on overall survival in stage II and stage III colon cancer: A propensity-score matched analysis of the National Cancer Database.
Authors: Nir Horesh, Sameh Hany Emile, Michael Freund, Zoe Garoufalia, Rachel Gefen, Peige Zhou, Arun Nagarajan, Steven D Wexner
Journal: Journal of Clinical Oncology (2023)

e15632 Background: Neoadjuvant chemotherapy (NAC) is currently indicated for patients with advanced colon cancer. However, there are little data regarding the impact of NAC on short-term outcomes and overall survival (OS). This study aimed to determine the role of NAC in patients with advanced colon cancer. Methods: A retrospective analysis of all patients with stage II-III colonic adenocarcinoma in the US National Cancer Database (NCDB) between 2006 and 2019. Propensity score matching was used to adjust for possible confounders. The cohort was divided into two equally matched groups: patients who received NAC and controls. The primary outcome was 5-year OS. Results: 902 (1.6% of the original cohort) patients with clinical stage II-III colonic adenocarcinoma were treated with NAC. Before matching, patients treated with NAC were significantly younger (61 vs 76 years; p &lt; 0.001) and more often male (54.5% vs. 46.5%; p &lt; 0.001) and had more private insurance (46.9% vs 22.6%; p &lt; 0.001) and a lower Charlson comorbidity index score (p &lt; 0.001). In addition, patients treated with NAC had more left-sided tumors (41.7% vs 30.1%; p &lt; 0.001) and underwent more resections of a contiguous organ with colonic resection (27.1% vs 7.6%; p &lt; 0.001). After matching, 620 patients were included in each group. The mean OS of patients in the NAC group was comparable to the control group (105.2 months, 95%CI: 98.1-112.2 vs 105 months, 95%CI: 98.2-111.7; p = 0.627). Stratifying OS based on clinical stage demonstrated that mean OS was significantly longer in patients with stage III (100.8 months, 95%CI 92.6-109.1 vs 88.4 months, 95%CI 79.7-97.1; p = 0.01), while the opposite effect was noted in stage II patients (106.1 months, 95%CI 96-116.3 vs 119.8 months, 95%CI 110.5-129.2; p = 0.04). Cox regression survival analysis showed that NAC was significantly associated with a lower risk of mortality (HR 0.72, 95%CI 0.64-0.8; p &lt; 0.001). Conclusions: Preoperative neoadjuvant chemotherapy is associated with improved OS in patients with Stage III colon cancer, but not in patients with stage II disease.
Electronic frailty index to assess post-operative healthcare utilization in veterans with non-metastatic colon cancer.
Authors: Huili Zhu, Javad Razjouyan, Sudha Yarlagadda, Yvonne H Sada
Journal: Journal of Clinical Oncology (2023)

e15642 Background: Frailty is a measure of physiologic reserve and is associated with adverse perioperative outcomes in patients with cancer. Existing surgical frailty measures, such as the 11-factor and 5-factor modified frailty index, may not be routinely utilized due to time constraints. Electronic Frailty Index (EFI) serves as an efficient and automated alternative. There is limited data for the use of EFI in assessment of post-operative healthcare utilization in patients with non-metastatic colon cancer. Methods: We performed a retrospective cohort study using VA administrative files from 2016 -2020 and VA Central Cancer Registry. EFI was calculated based on the Veterans Affairs-FI (VA-FI), a validated 31-item cumulative deficit FI, to define three groups: robust (≤ 0.1), prefrail (0.1 - 0.2), and frail ( &gt; 0.2). Cox proportional hazard analyses were conducted to evaluate survival. Logistic regression analyses were performed to examine healthcare utilization. All models were adjusted for age, gender, race, stage, and Charlson Comorbidity Index. Confidence intervals (CI) were calculated as 95%. Results: Among 2,861 patients (median age 70.7 ± 9.1 years) with stage I – III colon cancer who underwent surgery, 42.5% were robust, 36.6% were prefrail, and 20.8% were frail. The cohort was comprised of stage I (32.9%), stage II (34.9%), and stage III (32.2%) cases. Prefrail patients were at increased odds of emergency room (ER)/urgent care (UC) use at one year (adjusted odds ratio [aOR] 1.41, CI 1.09 – 1.83) compared to robust patients. Frail patients had an increased odds of ER/UC visits at 30 days (aOR 1.95, CI 1.19 - 3.20), 60 days (aOR 2.18, CI 1.42 - 3.34), and one year (aOR 2.79, CI 2.06 - 3.78). Increased risk of death was found in prefrail (adjusted hazard ratio [aHR] 1.34; CI 1.12 - 1.59) and frail (aHR 2.38; CI 1.97 - 2.86) patients when compared to robust patients. Conclusions: EFI was significantly associated with higher ER/UC utilization among frail patients with colon cancer who received curative intent surgery, independent of stage. Pre-frail and frail patients had worse survival outcomes compared to robust patients. Further work is needed to develop EFI as a risk-stratification tool in curative intent patients with colon cancer prior to surgery.
Discovery of gene fusions in driver-negative NCI-MATCH screening samples.
Authors: Stefan T Kaluziak, A. JOHN Iafrate, Chris Alan Karlovich, P. Mickey Williams, Jeffrey Sklar, Lisa McShane, Elizabeth Codd, Rashi Purohit, Grace Kirkpatrick
Journal: Journal of Clinical Oncology (2023)

3112 Background: NCI-MATCH aimed to determine the treatment efficacy of identifying actionable genetic alterations, irrespective of cancer histology, and to tailor treatment to the putative molecular drivers of tumors. Leveraging next-generation sequencing (NGS) and ThermoFisher’s Oncomine assay, this phase II trial genotyped 5,540 patient samples during active screening. Reviewing the genotyping statistics, we noted that NCI-MATCH identified fusions in 164 tumors, only 2.96%. This result is substantially lower than expected, given that clinical assays used at MGH’s and Yale’s diagnostic laboratories identified fusions in 8.5% of the 7,500 sequenced cases, 2.5% of which were novel. Notably, the Oncomine assay, based on multiplexed PCR, is unable to detect driver fusion events when either of the gene partners are unknown, or a novel breakpoint is involved. Cross-referencing identified fusions from MGH’s cohort with Oncomine’s primers, 5-30% of these fusions were potentially missed, suggesting that we could detect up to 30% more fusions than originally identified. Developed at MGH’s Molecular Diagnostics Laboratory, Anchored Multiplex PCR (AMP) interrogates 138 known fusion partners, enabling unbiased fusion detection when only one partner is known. With a high likelihood of identifying novel fusion drivers using AMP technology, we sequenced 663 cases that had no identified mutations of interest (MOI) from the NCI-MATCH cohort. Methods: A total of 200ng of RNA per sample was shipped from ECOG-ACRIN’s repository at MD Anderson Cancer Center to MGH (n = 319) and Yale (n = 349). Samples were processed with ArcherDX’s FusionPlex Pan Solid Tumor v2 kit and sequenced on the NextSeq500 with 150 base pair (bp) Paired-End (PE) kits. Data analysis was completed with ArcherDX’s analytics platform in conjunction with custom Python and R code. Reported fusions were manually verified on a case-by-case basis. All statistical tests were conducted in R. Results: Of the cases sequenced, most (663/693, 95.7%) were successfully processed with AMP. We identified 142 cases with at least one gene fusion out of 663 MOI-Negative cases (21%; 95% CI [18%, 25%]), with 90 as unique fusions, significantly more than the 8.5% observed at MGH (P &lt; .001). Of the 142 fusion-positive cases, 36 have potentially actionable driver events, 27 contain novel fusions not previously described, and in 63 cases no drugs are available to target either component of the fusion. Additionally, we identified fusions in (12/34, 35%) Cholangiocarcinoma and (38/101, 37.6%) Sarcoma cases, 9 and 3 of which were potentially actionable respectively. Conclusions: As hypothesized, we identified fusions that the NCI-MATCH screening had missed, detailing sequencing technology improvement that could be broadly applicable to many clinical laboratories sequencing tumors. Clinical trial information: NCT02465060 .
Alliance A021804: A prospective, multi-institutional phase II trial evaluating temozolomide versus temozolomide and olaparib for advanced pheochromocytoma and paraganglioma.
Authors: Jaydira Del Rivero, Kimberly Perez, Susan Michelle Geyer, Maged F. Khalil, Aishwarya Vijendran, Andrea Kordaris-Corkill, Ardaman Shergill, Kristen Renee Spencer, Heloisa P. Soares, Charles D. Lopez, Andrew B. Nixon, Amylou C. Dueck, Jeffrey A. Meyerhardt, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2023)

TPS4191 Background: Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors (NETs) that arise from chromaffin cells. Few antitumor therapies have been developed for patients (pts) with advanced PHEO/PGLs (APP). Potent poly (ADP-ribose) polymerase (PARP) is activated after DNA damage and regulates base excision repair, homologous recombination and non-homologous end joining. Inhibition of PARP enzymatic activity blocks PARP-mediated DNA repair, therefore PARP inhibitors can be directly cytotoxic to tumor cells which then permits synergy with agents that increase prevalence of single-strand breaks in tumor models. Temozolomide (TMZ) is an alkylating agent that induces single-strand DNA breaks and therefore is an optimal therapeutic pair with a PARP inhibitor. We are conducting a phase II multi-institutional study to evaluate the antitumor activity of TMZ and olaparib [OLA (a PARP inhibitor)] in patients with APP. Methods: Patients with APP with radiographic evidence of disease progression by RECIST v1.1 in the 12 months prior to registration can be enrolled in this phase II randomized study. Patients will be randomized in a 2:1 allocation with more patients to Arm 1. Arm 1 will receive TMZ 75 mg/m2 daily and OLA 200 mg twice daily on days 1-7 of a 21-day cycle. Arm 2 will receive TMZ 200 mg/m2 daily on days 1-5 of a 28-day cycle. Treatment on Arm 1 will continue for 13 cycles, followed by OLA maintenance until disease progression. Treatment on Arm 2 will continue for 13 cycles or until disease progression. The primary objective is to compare the progression-free survival between the two arms with a planned interim analysis for futility. Secondary endpoints include safety, response rate, and overall survival. Correlative endpoints include biochemical response and biomolecular markers (germline succinyl dehydrogenase mutations and tumor status of the repair enzyme methylguanine-DNA methyltransferase). We anticipate a null PFS median of approximately 5.4 months. We plan to accrue a total of 76 patients (randomized at a rate of 2:1 with more patients enrolled to the TMZ+OLA arm) in 38 months with a minimum follow-up of 2.5 months to achieve 56 PFS events. This design includes one interim analysis for futility using Rho Family spending functions (Rho = 2.5) and will yield 89% power to detect a hazard ratio (HR) of 0.5 (median PFS of 5.4 vs. 10.8 months) assuming exponential survival and using a one-sided log-rank test with type I error rate of 0.11. Clinical trial information: NCT04394858 .
Patient expectations and understanding of treatment intent in Belize.
Authors: James Dickerson, Wayne Wong, Alec Ohanian, Marta Habet, Margaret Bernard, Franklin W. Huang, Ramoncito Argenes Yacab
Journal: Journal of Clinical Oncology (2023)

e24188 Background: Discordance between patient understanding and physician recorded treatment intent is well documented in high income countries. A large fraction of patients report their palliative intent therapy is curative. We sought to find the discordance rate between patient and physician reported intent in Belize, a low- and middle-income country (LMIC) with a single public oncology clinic, founded in 2018, staffed by a single bilingual medical oncologist who is undertaking additional training in palliative care. In 2022, we surveyed established patients on chemotherapy to assess their understanding of treatment purpose. Methods: Approval was obtained at the Karl Heusner Memorial Hospital and the University of Rochester IRB prior to the study. Between February and March 2022, patients who consented were given a 21-question survey. Here we report on one portion of this survey. Patients with both patient and physician reported data were compared with a McNamar's exact test; a pre-specified exact logistic regression was run to examine potential predictors of patient/provider discordance (age, race, number of days from first chemotherapy to survey administration, patient's primary language). A p-value of 0.05 was used for significance. Results: 29 surveyed patients had both physician- and patient-reported treatment intent; surveys were administered a median of 42 days after first chemotherapy (IQR 26 – 116). 61% (18 of 29) of the sample was on palliative intent treatment. Median age was 51 (IQR 43 – 62) and cancer types were as follows: 45% breast, 24% GI, 24% gynecological, 3.4% head/neck, 3.4% lymphoma. 97% agreed their doctor spoke medical language they understand and 90% agreed they had enough information about their treatment. 31% mis-classified their treatment intent (p = 0.004). All 9 patients who mis-classified stated their palliative intent treatment was curative; this was 50% (9 of 18) of the palliative intent patients. We found no relationship between patient/provider discordance and age, race, number of days from first chemotherapy to survey administration, or patient’s primary language. Conclusions: We surveyed cancer patients in Belize and found that half of the patients on palliative intent therapy thought their treatment was curative. Despite this gap in understanding, 97% reported they understood the medical language being spoken and 90% of the patients agreed that they had good knowledge of their treatment. The amount of discordance described here is similar to reports in high income countries. Most palliative care, and palliative care research, is performed in high income settings. Implementation research with the aim of reducing physician/patient discordance in high-income countries should consider design elements that allow for adaptation to LMICs.
Phase 2, multicenter, open-label basket trial of <i>nab</i>-sirolimus for patients with malignant solid tumors harboring pathogenic inactivating alterations in <i>TSC1</i> or <i>TSC2</i> genes (PRECISION I).
Authors: Gopa Iyer, Dustin A. Deming, Michael J. Demeure, Noah Federman, Meredith McKean, Elizabeth Katherine Lee, Alexander I. Spira, David J. Kwiatkowski, Maen A. Hussein, Erlinda Maria Gordon, David G. Crockett, Kristen N. Ganjoo, Brian Schulte, Lee D. Cranmer, Li Ding, Anita N. Schmid, Willis H. Navarro, Jordi Rodon Ahnert
Journal: Journal of Clinical Oncology (2023)

TPS3168 Background: nab-Sirolimus is a novel albumin-bound mTOR inhibitor (mTORi) approved in the US for adult patients with malignant PEComa. In an exploratory analysis of the pivotal AMPECT trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with inactivating alterations in TSC2 and TSC1, respectively, had confirmed response (Wagner, J Clin Oncol, 2021). TSC1 and TSC2 alterations have been observed in patients with a broad variety of cancers. Most treatment-related adverse events in AMPECT were grade 1/2 (none were grade ≥4) and were consistent with mTORi class adverse events. Methods: PRECISION I (NCT05103358) will evaluate efficacy and safety of nab-sirolimus in patients with TSC1 (Arm A) and TSC2 (Arm B) alterations. Eligible patients are ≥12 y old and mTORi-naïve, possess malignant solid tumors with TSC1/TSC2 inactivating alterations (confirmed by central review of sequencing reports), and have received appropriate standard treatments, per investigator. nab-Sirolimus 100 mg/m 2 will be given weekly intravenously over 30 min on Days 1 and 8 of each 21-d cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using RECIST v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Enrollment began March 2022. Collaboration with leading next-generation sequencing vendors will expedite the identification of patients with qualifying TSC1/TSC2 mutations; study access will be facilitated through a just-in-time approach to trial location activation. Based on the prevalence of TSC1/TSC2 inactivating alterations, the most frequent tumor types expected are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric (Table). Clinical trial information: NCT05103358 . [Table: see text]
Real world data of apalutamid in the treatment of prostate cancer: Data of the German multicenter AmPel trial.
Authors: Axel Hegele, Stefan Schultheis, Lennart Skrobek, Sebastian Hollwegs, Jost Weber, Martin Ludwig, Anke Bartsch-Polle, Manfred Maywurm, Petra Huwe, Samuel Khalil, Rainer Häußermann, Markus Thiemer, Denny Varughese
Journal: Journal of Clinical Oncology (2023)

e17073 Background: Apalutamide (Apa) is a competitive inhibitor of the androgen receptor binding directly to the ligand-binding domain. In metastatic castration-sensitive prostate cancer (mCSPC) as well as non-metastatic castration-resistant prostate cancer (nmCRPC) Apa demonstrated a survival benefit in Phase-III trials. Nevertheless Real World data are still lacking. Methods: In the retrospective, multicenter AmPel trial (Apalutamid in prostate cancer in middle-Hessen) data of mCSPC and nmCRPC pat were collected before and during Apa treatment in routine clinical practice. Beside pat and tumor specific data side-effects, dose-modifications, response and subsequent therapies were assessed. Results: To date 100 pat were included since 11/2021. General data are summarized in table 1. mCSPC (n = 74): mFU 10 month (1-30). 75% showed mets at initial diagnosis: 56% with osseous, 15% with viszeral and 29% with oss/visz mets. PSA before therapy 13.5 ng/ml decreased to 0.2 ng/ml (-98.9%) after 3 mo. 77.4% showed a PSA decrease &gt; 90% and 49% a PSA level of &lt; 0.2 ng/ml after 6 mo. AEs ≥ 3: 12.3%. In 12.3% dose reduction was necessary. In 21% therapy was stopped due to toxicity (10.9%), progression (5.5%) and patient will (5.5%). 3 patients died: 1 due to PCA progression. PFS is not reached. nmCRPC (n = 26): mFU 15 month (3-30). Time after initial diagnosis: 6 y (1-22). PSA-Doubling time 3.9 mo (1-10). PSA before therapy 7.2 ng/ml with a decrease of 94.7% after 3 mo (0.45 ng/ml) and 62.5% with a PSA decrease &gt; 90%. AEs ≥3: 5%. In 15.4% dose-reduction was necessary. In 24% therapy was stopped due to toxicity (5%), progression (9.5%) and patient will (9.5%). MFS is not reached. No increased adverse events were observed in case of statin and anticoagulant medication. Conclusions: Compared to Phase III trials this first real-world data of the AmPel-trial showed treatment of older and more co-morbid mCSPC and nmCRPC patients in clinical practice. Apa treatment resulted in a rapid PSA-response, was safe and effective with tolerable and manageable side effects in real world unselected patients. PSMA-PET/CT is not used in daily practice as well as Conference decisions before therapy. Updated data of the ongoing AmPel trial will be presented. [Table: see text]